Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.     

普通及合并白癜风的HBV感染者血清抗TRP-1抗体的检测及其临床意义分析

目的 检测普通及合并白癜风的HBV感染者血清抗酪氨酸酶相关蛋白-1自身抗体(autoantibodies to tyrosinaserelated protein-1,a-TRP-1)水平并分析其临床意义.方法 选取白癜风患者126例(其中合并HBV感染8例,合并a-TP0、a-TG阳性34例,其他白癜风病84例);无白癜风病史的普通HBV感染者84例(HbsAg、HbeAg、HbcAb阳性24例,HbsAg、HbeAb、HbcAb阳性60例);乙肝抗体阳性对照者96例(HbsAb、HbeAb、HbcAb阳性48例,HbsAb阳性48例);乙肝五项全阴性的健康对照者96例.用ELISA法和细胞免疫荧光法检测所有标本a-TRP-1表达水平,并对结果进行统计分析.结果 白癜风组a-TRP-1总阳性率为6.3％ (8/126),其中合并HBV感染者、合并a-TPO及a-TG阳性者、其他白癜风患者a-TRP-1浓度为分别为948.2±68.3 U/mL、36.1±0.1U/mL、54.3±12.8U/mL,各组阳性率分别为100％ (8/8)、0％ (0/34)、0％(0/84);健康对照组为46.9±0.1U/mL,阳性率为0％(0/96).白癜风组中合并HBV感染者与健康对照组抗体浓度比较,差异有统计学意义(P＜0.01),而a-TPO、a-TG阳性者、其他白癜风患者与健康对照组比较差异无统计学意义(P＞0.05).普通HBV感染组中,HbsAg、HbeAg、HbcAb阳性者与HbsAg、HbeAb、HbcAb阳性者a-TRP-1浓度分别为868.7±161.4U/mL、756.7±157.5U/mL,阳性率分别为91.7％ (22/24)、85.0％ (51/60),与健康对照组比较,差异均有统计学意义(P＜0.01);乙肝抗体阳性对照组中HbsAb、HbeAb、HbcAb阳性者与HbsAb阳性者分别为26.8±0.1U/mL、33.3±0.1U/mL,阳性率分别为0％ (0/48)、0％ (0/48),与健康对照组比较,差异均无统计学意义(P＞0.05).细胞免疫荧光法检测结果显示,ELISA法检测的a-TRP-1抗体阳性血清与黑素细胞培养固定物反应后,在胞浆和胞膜处发出明亮荧光,荧光强度+++～++++,合并a-TPO、a-TG阳性及部分其他白癜风患者血清在胞膜处也有荧光,荧光强度约++,健康对照血清荧光暗淡或无荧光.结论 a-TRP-1抗体的高表达与HBV感染有密切关系,该抗体应该不是大部分白癜风患者具有代表性的血清标志物,在大部分没有白癜风的普通HBV感染者体内也可高水平存在,这可能是该类患者继发白癜风的预兆和重要原因.     

胰岛自身抗体与1型糖尿病

1617例糖尿病患者中自身抗体阳性率29．7％。单一抗体的阳性率明显低于3种抗体联合检测。多种胰岛自身抗体联合检测可提高1型糖尿病早期诊断的敏感性。谷氨酸脱羧酶抗体为成年糖尿病患者预示胰岛素依赖的较好的筛查试验，与酪氨酸蛋白磷酸酶抗体联合检测可达近100％的预报价值；而青少年糖尿病患者则还需检测胰岛细胞抗体。     

Stability of autoantibodies and their relation to genetic and metabolic markers of Type I diabetes in initially unaffected schoolchildren

Aims/hypothesis. To study temporal changes in positivity for autoantibodies associated with Type I (insulin-dependent) diabetes mellitus and the relations between these antibodies, HLA-DQB1-risk markers and first-phase insulin response (FPIR) in non-diabetic schoolchildren.¶Methods. The stability of the antibody status over 2 years was assessed in 104 schoolchildren initially positive for islet cell antibodies (ICA) or antibodies to the 65 000 M_r isoform of the glutamic acid decarboxylase (GADA) or both and in 104 antibody-negative control children matched for sex, age and place of residence. All children were also studied for their first-phase insulin response and HLA-DQB1 alleles on the second occasion.¶Results. On the second occasion 3 of the 98 initially ICA-positive children, 3/13 of those positive for antibodies to the IA-2 protein (IA-2A), 1/17 GADA-positive and 2/7 of those positive for insulin autoantibodies (IAA) tested negative for these antibodies. Children with IA-2A, GADA, IAA and multiple ( ≥ 2) antibodies had significantly lower first-phase insulin responses than the control children. In contrast, these responses did not differ between subjects with and without specific HLA-DQB1-risk alleles or genotypes. Of the six subjects with a considerably reduced first-phase insulin response three had multiple antibodies on both occasions but none of them had a DQB1 genotype conferring increased diabetes risk. Two subjects progressed to Type I diabetes within 3.4 years of follow-up, both of them having multiple antibodies and a considerably reduced first-phase insulin response but neither of them having a DQB1-risk genotype.¶Conclusions/interpretation. Positivity for diabetes-associated autoantibodies is a relatively stable phenomenon in unaffected schoolchildren, although conversion to seronegativity can occur occasionally. Our observations also indicate that DQB1 alleles associated with decreased susceptibility to Type I diabetes do not protect from impaired beta-cell function or from progression to overt disease in initially unaffected schoolchildren. [Diabetologia (2000) 43: 457–464]     

A Monoclonal Antibody-Based Characterization of Autoantibodies against Glutamic Acid Decarboxylase in Adults with Latent Autoimmune Diabetes

Autoantibodies to glutamic acid decarboxylase (GAD) are an important marker of the autoimmune-mediated beta-cell destruction in insulin-dependent (Type 1) diabetes. However, these autoantibodies are also found in patients with Stiff-man syndrome (SMS) without onset of diabetes and some diabetic patients who initially present as non-insulin dependent (Type 11) diabetes later becoming insulin-dependent, called as latent autoimmune diabetes in adults (LADA). To study the immune response to GAD in these LADA patients a competitive radiobinding assay based on murine monoclonal antibodies recognizing three different GAD regions was performed. The monoclonal antibodies against GAD recognize two different linear epitopes localized at the N- (amino acids 4-17) and C-terminus (amino acids 572-585) and one conformation-dependent epitope region (amino acids 221-442 IDDM-El) known to be immunodominant for diabetes-associated autoantibodies. All LADA sera (20/20) reduced substantially the ¹²⁵I-GAD binding of the monoclonal antibodies reactive with the conformation-dependent epitope region IDDM-El and only 20% of these sera additionally diminished the ¹²⁵I-GAD65 binding by those monoclonals reactive with the both linear epitopes. The SMS sera completely abolished the GAD binding of all three monoclonals, reflecting a broader repertoire including an immune response against the IDDM-El, a conformation-dependent GAD65 epitope region, also revealed if the SMS sera are diluted to equivalent antibody concentrations. In summary, our results show that diabetes-associated GAD autoantibodies even in adult patients with a late autoimmune process preferentially recognize a conformation-dependent middle GAD65 region. An immune response to all three GAD epitope regions is seldom in these LADA patients and only detectable in association with high antibody titres.     

The Prevalence of Anti-acetylcholinesterase Antibodies in Autoimmune Disease

A robust and precise enzyme linked immunosorbent assay (ELISA) with proven sensitivity and specificity has been employed to detect human antibodies (allogenic/autogenic) to human acetylcholinesterase (AChE). The sensitivity of the method has been established using mouse monoclonal antibodies (0.8?ng/ml) and uniquely, human sera positive for anti-Yt^a allogenic antibodies, to one phenotypic form (most common) of human AChE. The latter was also used as the positive human control to ensure functionality of the assay. The ELISA method was used to establish a normal distribution curve for absorbance values employing sera from healthy blood donors Subsequently, the ELISA was employed to investigate the prevalence of anti-AChE antibodies in patients with confirmed autoimmune disease and patients with non-autoimmune thyroid disease (diseased control). The results indicate that there is not a high prevalence of anti-AChE antibodies in patients with confirmed autoimmune disease. The lack of anti-AChE autoantibodies in patients' with clinically apparent Graves' ophthalmopathy, mitigates against there being a causal role of such antibodies in Graves' associated eye disease.     

Clinical correlates of monospecific anti-PM75 and anti-PM100 antibodies in a tri-nation cohort of 1574 systemic sclerosis subjects

Abstract

Objective: Autoantibodies directed against the two principal antigens of the human exosome complex, PM75 and PM100, are present in systemic sclerosis (SSc) sera and have been associated with myositis and calcinosis. However, there is a paucity of data on the clinical correlates of these autoantibodies separately and in the absence of other SSc-specific antibodies. The aim of this study was to assess the clinical correlates of monospecific anti-PM75 and anti-PM100 in SSc. Methods: A tri-nation cohort of 1574 SSc subjects was formed, clinical variables were harmonized and sera were tested for anti-PM75 and anti-PM100 antibodies using a line immunoassay. Results: Forty-eight (3.0%) subjects had antibodies against PM75 and 18 (1.1%) against PM100. However, only 16 (1%) had monospecific anti-PM75 antibodies and 11 (0.7%) monospecific anti-PM100 antibodies (i.e. in isolation of each other and other SSc-specific antibodies). Monospecific profiles of each autoantibody included more calcinosis. An increased frequency of myositis was only seen in subjects positive for both anti-PM75 and anti-PM100 antibodies. Lung disease was only associated with anti-PM75 and subjects with anti-PM100 antibodies had better survival compared to other antibody subsets. Conclusion: The prevalence of monospecific anti-PM75 and anti-PM100 antibodies in this large SSc cohort was low. Disease features associated with anti-PM/Scl antibodies may depend on particular and possibly multiple antigen specificities. However, due to the small samples, these results need to be interpreted with caution. International collaborations are key to understanding the clinical correlates of uncommon serological profiles in SSc.     

Anti-Soluble Liver Antigen (SLA) Antibodies in Chronic HCV Infection

Hepatitis C infection is associated with autoimmune disorders, such as the production of autoantibodies. Anti-LKM1 and anti-LC1, immunomarkers of type 2 autoimmune hepatitis, have been previously associated with a HCV infection. Anti-Soluble-Liver-Antigen autoantibodies (SLA) are specifically associated with type 1 and type 2 autoimmune hepatitis and more closely related to patients who relapse after steroid therapy. The recent molecular cloning of the soluble liver antigen provides the opportunity to develop more specific tests for the detection of antibodies against it. The aim of this work is to characterize anti-soluble-liver autoantibodies in sera from patients chronically infected by HCV. A recombinant cDNA from activated Jurkat cells coding for the full length tRNP^(Ser)Sec/SLA antigen was obtained. ELISA, Western Blot and immunoprecipitation tests were developed and used to search for linear and conformational epitopes recognized by anti-SLA antibodies in sera from patients chronically infected by HCV. Anti-soluble liver antigen antibodies were found in sera from 10.4% of HCV-infected patients. The prevalence was significantly increased to 27% when anti-LKM1 was also present. Most anti-SLA reactivity was directed against conformational epitopes on the antigen. The means titers by ELISA were lower than those obtained in type 2 AIH. The result of autoantibody isotyping showed a subclass restriction to IgG1 and also IgG4. This study shows the presence of anti-SLA antibodies in approximately 10% of HCV infected patients. The prevalence of SLA autoantibodies in HCV infected patients increases when LKM1 autoantibodies are also present. The relationship between the prevalence of this characteristic autoimmune hepatitis autoantibody and the implication of an autoimmune phenomenon in the liver injury of patients chronically infected by HCV needs further investigation.